Analysis of Pleiotropic Transcriptional Profiles A Case Study of DNA Gyrase Inhibition 英文参考文献.docVIP

AnalysisofPleiotropicTranscriptionalProfiles: ACaseStudyofDNAGyraseInhibition Kyeong Soo Jeong1,2,Yang Xie2,3,Hiroshi Hiasa4,Arkady B.Khodursky1,2* 1 Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, St. Paul, Minnesota, United States of America, 2 Biotechnology Institute, UniversityofMinnesota,St.Paul,Minnesota,UnitedStatesofAmerica,3DivisionofBiostatistics,SchoolofPublicHealth,UniversityofMinnesota,Minneapolis,Minnesota, UnitedStatesofAmerica,4DepartmentofPharmacology,UniversityofMinnesotaMedicalSchool,Minneapolis,Minnesota,UnitedStatesofAmerica Geneticandenvironmentalperturbationsoftenresultincomplextranscriptionalresponsesinvolvingmultiplegenes and regulons. In order to understand the nature of a response, one has to account for the contribution of the downstreameffectstotheformationofaresponse.Suchanalysiscanbecarriedoutwithinastatisticalframeworkin whichtheindividualeffectsareindependentlycollectedandthencombinedwithinalinearmodel.Here,wemodeled the contribution of DNA replication, supercoiling, and repair to the transcriptional response of inhibition of the Escherichia coli gyrase. By representing the gyrase inhibition as a true pleiotropic phenomenon, we were able to demonstrate that: (1) DNA replication is required for the formation of spatial transcriptional domains; (2) the transcriptional response to the gyrase inhibition is coordinated between at least two modules involved in DNA maintenance,relaxationanddamageresponse;(3)thegeneswhosetranscriptionalresponsetothegyraseinhibition does not depend on the main relaxation activity of the cell can be classified on the basis of a GC excess in their upstream and coding sequences; and (4) relaxation by topoisomerase I dominates the transcriptional response, followedbytheeffectsofreplicationandRecA.Wefunctionallytestedtheeffectoftheinteractionbetweenrelaxation andrepairactivities,andfoundsupportforthemodelderivedfromthemicroarraydata.Weconcludethatmodeling compoundtranscrip